Rheumatoid arthritis (RA) has a cardinal symptom of multiple erosive osteoarthritis, and is also a systemic inflammatory disease with an unknown etiology, simultaneously disturbing multiple organs. RA progresses chronically with periods of repeated remission and exacerbation. Untreated RA causes a destruction and a deformation of joint, later presenting functional disorders of motor apparatus. Sometimes it threatens lives of patients. Consequently, patients with RA have to bear large, lifelong physical and mental burdens.
RA results in a large variety of symptoms, and the diagnostic criteria of the American College of Rheumatology are widely used for its diagnosis. However, development of an onset state of RA is generally very slow, requiring a period from several weeks to several months. According to a judgment by means of an existence of rheumatoid factor, which is an objective index in the diagnostic criteria of American College of Rheumatology, a positive rate is 33% within 3 months and around 88% even after 12 months or more [Chiryo, 73(3): 23-27, 1991]. This indicates that RA cannot be diagnosed definitively at present. An attempt to diagnose rheumatoid arthritis by detecting a serum rheumatoid arthritis associated antigen IgM in a patient through a reaction with recombinant antigen has been performed (JP-A-10-513257).
In a treatment of RA, a therapeutic procedure to be selected is generally varied depending on a progression stage of symptoms in the disease state. Generally, in an early stage during which a definite diagnosis cannot be made, a nonsteroidal antiinflammatory drug (NSAID) is administered; and in a case in which a definite diagnosis can be made, a disease-modifying antirheumatic drug (DMARD) is administered in addition to the NSAID. In particular in an early stage of RA onset, since it is difficult to make a definite diagnosis at present, the NSAID is administered, and at the same time, an effort is made to identify this disease from other rheumatic diseases including collagen disease, by carefully observing the symptom and procession. In a case in which the symptoms continue to progress, steroids may be administered, and a pharmacotherapy for pain together with a physiotherapy and an orthotic therapy are performed in order to maintain and ameliorate joint functions. In addition, in a case in which daily life is inconvenienced by a joint disruption, a surgical therapy may be performed.
Though aspects of arthritis and joint disruption, which are the causes of RA, in particular their pathological processes, are gradually being elucidated through a variety of studies, RA is still thought to be a disease which develops and progresses after an onset caused by cooperation with large number of causative factors including a living environment. For that reason, in order to perform a more exact elucidation of the disease and a proper therapy thereof, an essential part of interactions of the multiple factors involved has to be established. Since RA is a disease with an incident rate of 1% or less in the world (N. Engl. J. Med., 322: 1277-1289, 1990), but siblings of the patient develop the disease at a frequency of 8% or more (Cell, 85: 311-318, 1996), one of the causative factor is suspected to be some genetic factor. Further, since an environment is thought to be one of the causative factors, the onset may be delayed or prevented by paying attention to the daily life style such as diet, viral infections and stress, if the onset risk can be known in advance. Further, by making an earlier diagnosis and providing an appropriate treatment in an earlier stage, progression of RA can be delayed and prognosis can be expected to be improved.
In the international publication, WO98/51794, the inventors of the present invention performed linkage analyses of patients with RA and their sibs using a microsatellite marker, and identified three gene loci involved where genes causative of rheumatoid arthritis are positioned. The following causative genes have been identified:    (1) A gene causative of rheumatoid arthritis located no more than ±1 centimorgan apart from a DNA sequence hybridizable with microsatellite markers D1S214 and/or D1S253 in human chromosome 1.    (2) A gene causative of rheumatoid arthritis located no more than ±1 centimorgan apart from a DNA sequence hybridizable with microsatellite marker D8S556 in human chromosome 8.    (3) A gene causative of rheumatoid arthritis located no more than ±1 centimorgan apart from a DNA sequence hybridizable with microsatellite markers DXS1001, DXS1047, DXS1205, DXS1227 and/or DXS1232 in human chromosome X.
The present inventors further extended the study on the causative gene (3) described above, and found that a specific mutation (2 Exon deleted mutation) of the Db1 proto-oncogene of chromosome X [EMBO J. 7(8): 2465-2473, 1988] was related to the onset state of RA. They then filed the patent application (PCT/JP00/01697).
An object of the present invention is to elucidate further mutations in human Db1 gene and their relations to an onset or an onset risk of RA; and provides a method for precisely diagnosing the onset or the onset risk of RA by utilizing such mutations. Another object of the present invention is to provide a diagnostic kit useful for detecting a genomic DNA which is a mutated Db1 gene associating with RA.